Abstract 2888: Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins
Authors: Meredith L. Stone, Jesse Lee, Jae W. Lee, Heather Coho, Max M. Wattenberg, Hana Choi, Veronica M. Hererra, Yuqing Xue, Shaanti Choi-Bose, Vinod Balachandran, Gregory L. Beatty
Journal: Cancer Research (2023)

Abstract INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease for which the 5-year survival rate is about 10%. Rare long-term survivors after surgical resection have been characterized as having high quality immune responses to primary tumors. However, the mechanisms that regulate immune surveillance in PDAC remain ill-defined. METHODS: Here, we used patient data and genetic mouse models to study potential determinants of T cell surveillance in PDAC. SUMMARY: Long-term survivors (&amp;gt;3 years) compared to short-term survivors (&amp;gt;3 months and &amp;lt;1 year) after resection of treatment-naïve PDAC had increased CD8+ T cell infiltration into tumors and lower systemic inflammation as measured by neutrophil-to-lymphocyte ratio (NLR). In a panel of 10 PDAC cell lines orthotopically injected into mice, higher NLR correlated with decreased T cell infiltration into tumors and increased liver inflammation. Specifically, IL-6/STAT3 signaling was enriched in livers of mice with tumors with fewer T cells. Based on these observations, we hypothesized that pancreatic cancer development triggers liver-directed immunosuppression that restrains productive anti-tumor T cell surveillance. To test this hypothesis, we overexpressed IL-6 in hepatocytes, which was sufficient to convert a primary tumor with a T cell “inflamed” phenotype to T cell “non-inflamed”. This biology was dependent on STAT3 signaling in hepatocytes. To this end, loss of STAT3 specifically in hepatocytes drove an influx of CD8+ T cells into non-inflamed primary tumors. We next identified acute phase reactants serum amyloid A proteins 1 and 2 (SAA) as necessary for the inhibition of T cell infiltration by hepatocytes. In mice lacking SAA, tumor-specific T cell infiltration was increased, T cells in tumors expressed activation markers, and tumor growth was inhibited. In patients, we similarly found that high levels of SAA correlated with a decrease in T cells and an increase in monocytes in the peripheral blood; furthermore, long-term survivors after tumor resection had significantly lower SAA levels than short-term survivors. To test the direct role of SAA in survival after tumor resection, we developed a novel mouse model of distal pancreatectomy/splenectomy, which recapitulated observations from patients that higher T cell infiltration into tumors associates with improved survival. Further, mice lacking SAA survived significantly longer after surgery in a T cell-dependent manner. CONCLUSIONS: Our findings define a pivotal role for hepatocytes in regulating productive T cell surveillance in cancer. Specifically, our data show that IL-6 can activate STAT3 in hepatocytes to release SAA which then suppress productive T cell surveillance. Taken together, these data suggest that activation of hepatocytes and their release of SAA are novel therapeutic targets for improving the productivity of cancer immunity and patient outcomes after surgery. Citation Format: Meredith L. Stone, Jesse Lee, Jae W. Lee, Heather Coho, Max M. Wattenberg, Hana Choi, Veronica M. Hererra, Yuqing Xue, Shaanti Choi-Bose, Vinod Balachandran, Gregory L. Beatty. Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2888.